Article coatings including oligomerized polyphenol layer and biological methods of use

ABSTRACT

Embodiments of the disclosure include coatings comprising an oligomerized polyphenol layer. The oligomerized polyphenol layer can be used as an intermediate coated layer on a medical device that hydrogen bonds to a synthetic or natural polymer, which in turn can be used as a top coat or further associated with another coated layer. The multilayered coatings can provide properties such as hemocompatibility or lubricity. In other embodiments, the oligomerized polyphenol layer is used on a medical device as a hemostatic layer configured to contact blood and promote coagulation. The oligomerized polyphenol layer can also be used on the inner surface (e.g., inner diameter) of a medical device to prevent bacterial adherence. The oligomerized polyphenol layer can also be used on the surface of a in vitro diagnostic article, or a cell culture device to, promote adsorption of a biological molecule.

PRIORITY

The present non-provisional application claims the benefit of commonlyowned provisional Application having Ser. No. 62/035,173, filed on Aug.8, 2014, entitled ARTICLE COATINGS INCLUDING OLIGOMERIZED POLYPHENOLLAYER AND BIOLOGICAL METHODS OF USE, which Application is incorporatedherein by reference in its entirety.

FIELD

The present disclosure relates to coatings for medical, diagnostic, andcell culture articles.

SUMMARY OF THE INVENTION

Embodiments of the disclosure include coatings for various articles,such as medical, diagnostic, and cell culture articles. Embodiments ofthe disclosure also include methods using the coated articles.

Generally, the articles have a costing that includes a coated layer(e.g., a first coated layer) of oligomerized polyphenol. In someembodiments the articles have at least one different coated layer(s)(e.g., second) including a natural or synthetic polymer that hydrogenbonds with the oligomerized polyphenol. The coatings display desirableproperties, and the coating materials and techniques can be used toprovide well-formed coatings on various surfaces. The coated articlescan be used in various methods, such as methods associated with theimplantation of medical devices, the treatment of conditions using animplanted medical device, hemostatic methods including blood clottingand wound healing, in vitro diagnostic methods such as ELISAs, and cellculture methods.

The oligomerized polyphenol can comprise a polyphenol derived fromesterification of a composition comprising gallic acid. The oligomerizedpolyphenol can include, for example, oligomerized tannic acid.

In one embodiment, the disclosure provides a medical device comprising acoating, the coating comprising a first coated layer comprisingoligomerized polyphenol, and a second coated layer comprising asynthetic or natural polymer. In the coating the

synthetic or natural polymer is hydrogen bonded to the oligomerizedpolyphenol and the first coated layer is positioned between an articlesurface and the second coated layer.

The coating can be formed in a method comprising step of applying afirst coating composition comprising a polyphenol to a medical device. Afirst layer comprising oligomerized polyphenol is formed uponapplication. Next, a second coating composition comprising a syntheticor natural polymer is applied onto the first layer. The synthetic ornatural polymer becomes hydrogen bonded to the oligomerized polyphenol.

Medical devices having a first coated layer comprising oligomerizedpolyphenol include catheters and intravascular prosthesis. Inparticular, the polyphenol materials a, useful for coating innersurfaces of medical devices, such as the inner diameters of catheters.

Given its ability to provide coatings in a straightforward manner, thedisclosure also provides a medical device comprising an inner surfacecomprising a coating, the coating comprising oligomerized polyphenol.Additional coated layers (e.g., second coated layer) on the oligomerizedpolyphenol are optional. In one embodiment, the oligomerized polyphenolcoating is formed on the inner diameter of a catheter. The inner surfacecoating can be useful in a method for reducing or preventing theadherence of bacteria on a medical device surface, comprising implantingthe device of claim in a patient.

In another aspect of the disclosure, experimental studies revealed thatan oligomerized polyphenol coating was suprisingly beneficial forpromoting the adsorption of fibrinogen, and for promoting bloodclotting. Accordingly, the disclosure also provides a medical devicecomprising a hemostatic coating comprising oligomerized polyphenol, thedevice configured so the oligomerized polyphenol comes in contact with abody fluid.

In a related aspect, the disclosure provides a method for promotingclotting at a target location in or on the body comprising placing themedical device with the hemostatic coating comprising oligomerizedpolyphenol in or on a target location in the body, wherein the coatingcontacts body fluid and promotes clotting at the target location.

In another aspect, the disclosure provide an article configured for usein an in vitro diagnostic assay or cell culture, the article comprisinga coating comprising oligomerized polyphenol. The coating on sucharticles can be useful for adsorbing molecules for detection assays, orfor improving cell culture conditions.

In an associated aspect, the disclosure provides a method for promotingadsorption of a biological macromolecule to a surface of an article inan in vitro diagnostic assay or cell culture. The method includes stepsof contacting an article comprising a coating comprising oligomerizedpolyphenol with a composition comprising a biological macromolecule,wherein the coating promotes adsorption of the biological macromoleculeto the oligomerized polyphenol via hydrogen bonding.

BRIEF DESCRIPTION OF THE FIGURES

The disclosure may be more completely understood in connection with thefollowing drawings, in which:

FIG. 1A is a schematic view of cross section of a medical device havinga single layer oligomerized polyphenol coating.

FIG. 1B is a schematic view of cross section of a medical device havinga multi-layer coating with oligomerized polyphenol layer.

FIG. 2A is a schematic view of cross section of a medical device havinga multi-layer coating with oligomerized polyphenol layer.

FIG. 2B is a schematic view of cross section of a medical device havinga multi-layer coating with oligomerized polyphenol layer.

FIG. 3A is a schematic view of cross section of a medical device with alumen having a single layer oligomerized polyphenol coating on the innerdiameter of the device.

FIG. 3B is a schematic view of cross section of a medical device with alumen having a multi-layer coating on the inner diameter of the devicewith an oligomerized polyphenol layer.

FIG. 4 is a graph showing results of an assay of fibrinogen adsorptionon coated and uncoated substrates.

FIG. 5 is a graph showing results of an assay of plasma clotting time oncoated and uncoated substrates.

FIGS. 6A-D are graphs showing results of immunoassays on surfaces withand without tannic acid coatings.

While the disclosure is susceptible to various modifications andalternative forms, specifics thereof have been shown by way of exampleand drawings, and will be described in detail. It should be understood,however, that the disclosure is not limited to the particularembodiments described. On the contrary, the intention is to covermodifications, equivalents, and alternatives falling within the spiritand scope of the disclosure.

DETAILED DESCRIPTION OF THE ILLUSTRATIVE EMBODIMENTS

A “polyphenol” according to the disclosure, refers to an organicmolecule having two to up to about 20 phenolic units. Exemplarypolyphenols can optionally be characterized by one or more of thefollowing properties a non-polymeric molecule; a molecular weight in therange of about 200-5000 Da; 1-3 hydroxyl groups per phenolic unit, andhaving 5-8 aromatic rings per 1000 Da. Exemplary polyphenols include twoor more phenolic units linked together. Exemplary phenolic units areselected from resorcinol, pyrocatechol, pyrogallol, phloroglucinol, andmixtures thereof. The phenolic unit can linked via various chemicalgroups, such as ester groups, ether groups, or by C—C groups.

In some cases the polyphenol can be formed by the esterification of oneor more phenolic acid(s), such as gallic acid (3,4,5-trihydroxybenzoicacid), around a carbohydrate core, such as glucose. Tannic acid(compound A) is an example of one type of polyphenol that can be formedby such a reaction, and has the following structure:

In some cases the polyphenol is an ester of a phenolic acid(s), such asgallic acid, with another molecule containing phenolic and non-phenolichydroxyl groups, such as gallecatechol. Epigallocatechin-3-gallate(EGCG; compound B), epicatechin-3-gallate

(ECG; compound C); theaflavin-3-gallate (compound D), and ellagitannin(compound B); are examples of polyphenols formed from the esterificationof gallic acid with another molecule containing phenolic andnon-phenolic hydroxyl groups.

Another exemplary polyphenol is epigallocatechin:

A coating solution can be formed by including a polyphenol in a solvent.A single polyphenol, or a combination of polyphenols, can be dissolvedor suspended in a coating solution at a concentration suitable forforming a coating on the surface of an article. Exemplary concentrationsof polyphenol are in the range of about 1 ng/mL to about 10 mg/mL, orabout 0.5 mg/mL to about 5 mg/mL, such as about 2 mg/mL (e.g., tannicacid at about 2 mg/mL).

Coating of a substrate can be carried out various ways. In mane modes ofpractice, the polyphenol is dissolved or suspended in a coating solutionhaving a basic pH, such as above 7, such as in the range of about 7.5 toabout 9.5, or more specifically in the range of about 8.0 to 8.5.Exemplary basic coating solutions can be made using a solvent such aswater and a biocompatible base, such as sodium bicarbonate (e.g., atabout 0.5 M). Other biocompatible weak bases in include ammonia,ammonium hydroxide, urea, piperidine, imidazole, potassium carbonate,sodium carbonate, potassium bicarbonate, and pyridine, or combinationsthereof. In other modes of practice, the polyphenol can be dissolved orsuspended in a coating solution at a pH less than 7. To induceoligomerization of the polyphenol the pH of the solution cansubsequently be raised to an alkaline pH. Alternatively, a coatingsolution including the polyphenol in a solvent can be dip coated onto adevice, allowed to dry, and then put in a higher pH buffer to affectcrosslinking. The coating solution can also include a neutral salt, sucha sodium chloride, at a concentration in the range of about 0.15 M toabout 0.75 M, or more specifically at about 0.5 M.

If desired, one or more optional components can be included in thepolyphenol coating solution as long as the component(s) does notinterfere with the ability of the polyphenol to oligomerize and form acoated layer on the article surface. For example, the polyphenol costingsolution may optionally include one or more polymeric components, suchas polyamines, or poly(acrylic acid).

The first coating solution can be applied to a substrate. Prior toapplication of the first coating solution to the substrate, one or moreof many different pretreatment steps can be taken. In some embodiments,the surface of the substrate can be cleaned. For example, the surfacecan be wiped or dipped into an alcohol such as isopropyl alcohol. Insome embodiments, the substrate can be put into a detergent solutionsuch as a VALTRON® solution and sonicated. In some embodiments thesurface of the substrate can be sterilized.

Many different techniques can be used to apply the solution to thesubstrate. By way of example, exemplary techniques can include dropcoating, blade coating, dip coating, spray coating, and the like. In onemode of coating, the solution is applied by drop coating. In other modesof coating, the substrate can be immersed into the polyphenol coatingsolution for a period of time sufficient for the coated layer ofoligomerized polyphenol to form on the article surface. In exemplarymodes of practice the article is immersed in a polyphenol coatingsolution. The article is maintained in the solution for a period of timegreater than 5 seconds, greater than 1 minute, greater than 0 minutes,greater than 30 minutes, such as in the range of about 1 minute to about2 hours. The article can then be rinsed using a liquid such as water toremove any excess coating material(s).

The oligomerized polyphenol layer can be formed without requiring anoligomerization polymerization initiator, such as a light activatedpolymerization initiator. Therefore the coating solutions and processesare particularly useful to forming a coated layer on an article surfacethat where it is difficult to provide light. For example, the coatingsolutions and processes can be used to form an oligomerized polyphenollayer on a substrate having a complex geometry, or one having an innersurface, such as surfaces of medical devices. These inner surfaces maynot be accessible to other forms of energy, such as light, whichalternatively may be used to activate and bind coating reagents tosurfaces. Examples of substrates that have inner surfaces include, forexample, stets, catheters such as PTCA catheters and hemodialysiscatheters, hemodialysis membranes, and other devices having innersurfaces. These substrates can be formed, for example, from a complexarchitecture of materials, or contain many pores.

An “oligomerized” polyphenol layer refers to a water-insoluble coatedlayer including crosslinked polyphenol molecules. Without intending tobe bound by theory, the basic coating solution is believed to promoteoligomerization of the polyphenols and formation of an oligomerizedpolyphenol layer by oxidation of the polyphenol, deprotonation ofphenolic hydroxyl groups, rearrangement, and phenol-phenol crosslinkingvia the phenolic groups. The molecular mechanism of forming theoligomerized polyphenol layer is believed to resemble the formation of apolydopamine coating as described by Lee et al. (Science 318:426-430,2007).

In another mode of practice, an oligomerized polyphenol layer is formedby including in the coating composition an inorganic molecule that cancoordinate with chemical groups of the polyphenol molecules and therebyform crosslinks. For example, a metal ion such as iron (Fe) cancoordinate with deprotonated phenolic hydroxyl groups from up to threephenolic groups as taught by Ejima et al. (Science 318:426-430, 2007).

Embodiments of the disclosure include coatings that have an oligomerizedpolyphenol layer that comes in contact with a body fluid, a tissue, acomposition used for a detection analysis, or cell culture media. Theoligomerized polyphenol can serve to attach or bond one or morecomponents from body fluid (e.g., fibrinogen), or components from acomposition used for an in vitro assay (e.g., antibodies or analytes),or components from a cell culture composition.

As such, the oligomerized polyphenol layer can be sole coated layer inthe coating, or can be the “outermost” or “t p” layer if the coatingincludes more than one layer. Optional additional layer(s) may bebetween the oligomerized polyphenol layer and the device surface. FIG.1A is a coating embodiment wherein an oligomerized polyphenol layer 101is in direct contact with a device surface 102. FIG. 1B is a coatingembodiment wherein an oligomerized polyphenol layer 111 is the outermostlayer with a tie (or intermediate) layer 113 in contact with a devicesurface 112. FIG. 3A is a coating embodiment showing a cross section ofa medical device with a lumen (such as a catheter), wherein anoligomerized polyphenol layer 311 is present on the inner diameter of adevice surface 312. Exemplary substrate materials and materials foroptional tie or intermediate layers are known in the art.

The oligomerized polyphenol layer (e.g., 101, 111, or 311) can be verythin, such as less than 100 nm, less than 50 nm, less than 25 nm, lessthan 10 nm, less than 5 nm (upper limits), or greater than 0.1 nm,greater than 0.25 nm, greater than 0.5 nm, greater than 1 nm, greaterthan 2 nm (lower limits), or in a range of any combination of theselower and upper limits.

Experimental studies associated with the disclosure have shown theoligomerized polyphenol layer was able to promote significant fibrinogenadsorption (see FIG. 4). Fibrinogen is a protein factors involved in theclotting cascade, and its adherence to a coated surface of a medicaldevice that contacts blood can promote attachment of other coagulationfactors. Fibrinogen adhesion can be followed by fibrin and vonWillebrand factor (vWF) on the device surface, which may becharacterized by a loosely structured matrix. This phase can also becharacterized by platelet adhesion.

In addition, the polyphenol layer was able to promote shortened plasmaclotting times (see FIG. 5). Therefore, the oligomerized polyphenol perse, provides a useful surface modification for medical articlesdesirably having a hemostatic property. A “hemostatic” property refersto the ability to promote “hemostasis” which is the clotting of blood.Various medical articles or devices that are implanted or inserted inthe body, or that are placed in contact with a body tissue can beprovided with an oligomerized polyphenol hemostatic coating.

In some embodiments, the oligomerized polyphenol hemostatic coating isused in conjunction with an occlusion device for occluding any sort oftarget area within the body. Occlusion devices include implantablemedical devices that are delivered to a target area of the body and thatare intended to function to prevent movement of body fluids through orinto the area n which the device has been delivered. Thrombosis and theformation of a clot in association with the occlusion device generallyaid in establishing the hemostatic function. Occlusion can beestablished by delivering the device to a target area and allowing theoligomerized polyphenol hemostatic coating to promote formation offibrin clot, thereby physically occluding the target area. Occlusionarticles with an oligomerized polyphenol hemostatic coating can beuseful for the selective occlusive of vasculature, including arteries,veins, fistulas, aneurysms, fallopian tubes, bile ducts, and the like.The oligomerized polyphenol hemostatic coating can be used in connectionwith vascular occlusion coils, wires, or strings that can be insertedinto aneurysms.

An oligomerized polyphenol hemostatic coating can also be formed on aporous surface of a medical article. An article having a “poroussurface” refers to any article having a surface with pores on which anoligomerized polyphenol hemostatic coating can be formed. In some cases,the pores can be of a physical dimension that permits in-growth oftissue.

In many cases the porous surface of the article is a fabric or hasfabric-like qualities. The porous surface can be formed from textiles,which include woven materials, knitted materials, and braided materials.Particularly useful textile materials am woven materials which can beformed using any suitable weave pattern known in the art.

The porous surface can be that of a graft, sheath, cover, patch, sleeve,wrap, casing, and the like. These types of articles can function as themedical article itself or be used in conjunction with another part of amedical article. For example, the oligomerized polyphenol hemostaticcoating can be used in conjunction with fabrics, such as cardiacpatches, sheaths, and grafts. In these embodiments, a procoagulantcoating can be used to generate a hemostatic fibrin clot in associationwith the coated fabric. These coated articles can be used to prevent theflow of blood within the body in the location the coated article isintended to function.

Fabrics can be prepared from synthetic addition or condensation polymerssuch as polyesters, polypropylenes, polyethylenes, polyurethanes, andpolytetrafluoromethylenes. Polyethylene terephthalate (PET) is acommonly used polymer in fabrics. Blends of these polymers can also beutilized in the preparation of fibers, such as monofilament ormulti-filament fibers, for the construction of fabrics. Commonly usedfabrics include those such as nylon, velour, and DACRON™.

Surgical patches can be used in various medical procedures to preventblood flow. A surgical patch having the oligomerized polyphenolhemostatic coating can rapidly generating a fibrin clot associated withthe patch, thereby improving hemostatic function.

Other particular contemplated porous surfaces include those of cardiacpatches. These can be used to decrease suture line bleeding associatedwith cardiovascular reconstructions.

The oligomerized polyphenol layer can also be used as a coating on thesurface of an in vitro diagnostic article. The coating can be useful forpromoting the attachment of a biological molecule, such as a peptide,protein, nucleic acid, or polysaccharide, to the surface. The proteincan be an antibody or antibody fragment, or an analyte that is a peptideor protein.

The oligomerized polyphenol layer can be applied to the in vitrodiagnostic article over its entire surface, or over a selected portionor portions of the surface. For example, the oligomerized polyphenollayer may be applied in a certain pattern on the device surface topromote adsorption of the biological molecule according to the pattern.

The oligomerized polyphenol layer can be formed on any suitable assayarticle, such as an assay vessel, or portion thereof. An assay articlecan be any article on, or in which, analyte detection, such as by ELISA,can be performed. The assay article can be made from material such asglass (e.g., surface modified glass), quartz, silicon, metals, metaloxides or plastic, such as polystyrene, polyolefins, polypropylene, andpolycarbonate. Exemplary assay articles are single and multi-wellplates, such as medium and smaller-welled plastic plates such as 6, 24,96, 384, and 1536 well plates. These are commonly known in the art asmicrotiter plates, microplates, or microwell plates. Exemplary platesfor use in in vitro diagnostic assays in each well hold from microliterto milliliter volumes of liquid. Other types of assay vessels that canbe used for analysis include capillary tubes. The assay article havingan oligomerized polyphenol layer can optionally be included in a kit, orcan be supplied by the user to carry out an in vitro diagnostic assay.

The oligomerized polyphenol layer can promote adsorption of a biologicalmacromolecule to the coated surface. For example, in some modes ofpractice, an article having an oligomerized polyphenol coating iscontacted with an antibody-containing composition to promote adsorptionof the antibody to the oligomerized polyphenol via hydrogen bonding.Areas of the oligomerized polyphenol coating can then be blocked with apolymer, which can also associate via hydrogen bonding, to blocksubsequent non-specific analyte or antibody interaction. Theoligomerized polyphenol layer can also be used as a coating on thesurface of cell culture vessel. The coating can be useful forpassivating the surface of the vessel to prevent unwanted adsorption ofcomponents of the cell culture vessel wall. A passivating or cellbinding component, such as a synthetic or natural polymer, can behydrogen bonded to the oligomerized polyphenol layer. Alternately, thecoating could provide for attachment of components that promote cellattachment. Examples of components that provide promote cell attachmentinclude collagen, fibronectin, laminin, and cell adhesion-promotingpeptides such as ROD.

A “cell culture vessel” is an example of a cell culture article and, asused herein, means a receptacle that can be coated with an oligomerizedpolyphenol coating and can contain media for culturing a cell or tissue.The cell culture vessel may be made from a glass, plastic, or even frommetals, such as those metals used to make medical devices. Preferablythe plastic is non-cytotoxic. Exemplary cell culture vessels include,but are not limited to, single and multi-well plates, including 6 welland 12 well culture plates, and smaller welled culture plates such as96, 384, and 1536 well plates, culture jars, culture dishes, petridishes, culture flasks, culture plates, culture roller battles, cultureslides, including chambered and multi-chambered culture slides, culturetubes, coverslips, cups, spinner bottles, perfusion chambers,bioreactors, and fermenters.

In providing a coated cell culture vessel, a coating process, such asone described herein, can be used to provide an oligomerized polyphenolcoating to a wall of a cell culture vessel. The coating method isadvantageous for those vessels having surfaces wherein it is difficultto deliver light otherwise used for initiating a polymerizationinitiator. After a surface of the cell culture vessel is provided withan oligomerized polyphenol coating it can be contacted with acomposition that includes a material that can adsorb to the oligomerizedpolyphenol coating to passivate the surface and prevent non-specificbinding of cell culture components to the vessel. Alternatively, theadsorbed material can promote the binding of cells to the coatedsurface. Embodiments of the disclosure also include coatings that havean oligomerized polyphenol layer that is an intermediate layer. Theoligomerized polyphenol layer can be in direct contact with a devicesurface, in direct contact with a second coated layer that is distal tothe device surface, or both. One or more components of the second coatedlayer, such as a natural or synthetic polymer(s), can be hydrogen bondedto the oligomerized polyphenol layer

FIG. 2A is a coating embodiment wherein an oligomerized polyphenol layer201 is in direct contact with a device surface 202, and a second coatedlayer that includes a natural or synthetic polymer 204 is the outermostlayer. Hydrogen bonding between the oligomerized polyphenol and thenatural or synthetic polymer can be present at the interface betweenlayers 201 and 204. Optionally, a tie layer (not shown) can be presentbetween the oligomerized polyphenol layer 201 and the device surface202.

FIG. 2B is a coating embodiment wherein an oligomerized polyphenol layer211 is in direct contact with a device surface 212, an intermediatesecond coated layer 214 that includes a natural or synthetic polymer,and a third coated layer 215 is the outermost layer. Bonding between thenatural or synthetic polymer of the second coated layer 214 and acomponent of the third coated layer 215 may or may not exist. In somearrangements, there is hydrogen bonding between the natural or syntheticpolymer of the second coated layer 214 and a component of the thirdcoated layer 215.

FIG. 3B is a coating embodiment showing a cross section of a medicaldevice with a lumen (such as a catheter), wherein an oligomerizedpolyphenol layer 321 is present on the inner diameter of a devicesurface 322, the coating further comprising a layer 324 with a naturalor synthetic polymer that is hydrogen bonded to the oligomerizedpolyphenol.

Optionally, the costing can include additional coated layers (e.g.,fourth, fifth) that can be present as intermediate or outer coatedlayers on the device.

The thickness of a coating that includes the oligomerized polyphenollayer (e.g., 201 or 211) and second coated layer (e.g., 204, 214, 324)can vary depending on the coating materials and process used for formingthe coating. The coating can have a thickness of less than 2 μm, lessthan 1 μm, less than 500 nm, less than 250 nm, less than 100 nm (upperlimits), or greater than 1 nm, greater than 2.5 nm, greater than 5 nm,greater than 10 nm, greater than 25 nm (lower limits), or in a range ofany combination of these lower and upper limits. The costing canoptionally be described in terms of the ratio of the thickness of theoligomerized polyphenol layer (e.g., 201, 211, 321) and second coatedlayer (e.g., 204, 214, 324).

In some embodiments, the second layer includes a polymer capable ofbonding to the oligomerized polyphenol of the first coated layer. A testfor the ability of a polymer to hydrogen bond to the oligomerizedpolyphenol may be carried out by staining the coasting with toluidineblue and testing its durability.

Exemplary polymers include natural and synthetic polymers. Naturalpolymers include polysaccharides, polypeptides, and nucleic adds.Exemplary polysaccarides are methylcellulose and hydroxyethylcellulose.Exemplary synthetic polymers include poly(n-isopropylacrylamide),poly(n-vinylcaprolactam), poly(ethylene oxide), and poly(vinyl alcohol).

The natural or synthetic polymers can be dissolved or suspended in asecond coating composition, which can then be applied to theoligomerized polyphenol layer. In exemplary methods, the natural orsynthetic polymer is added to a polar solvent, such as water, in anamount in the range of about 0.5 mg/mL to about 50 mg/mL, about 2 mg/mLto about 40 mg/mL, or about 5 mg/mL to about 25 mg/mL. Examplarysolvents include water, alcohols (e.g., methanol, ethanol, n-propanoland isopropanol), amides (e.g., dimethylformamide, N-methylpyrrolidone),ethers (e.g., tetrahydrofuran (THF), dipropyl ether and dioxolane), andnitriles (e.g., acetonitrile).

The second coating composition can be applied to the first coated layerof oligomerized polyphenol in any suitable manner under conditions topromote hydrogen bonding of the polymer to the oligomerized polyphenol.Excess unbound polymer can be removed during a washing step.

In some embodiments, the second layer includes a vinyl pyrrolidonepolymer. As used herein a “vinyl pyrrolidone polymer” refers to polymersincluding vinyl pyrrolidone monomeric units. The vinyl pyrrolidonepolymer can be a vinyl pyrolidone homopolymer or a vinyl pyrrolidonecopolymer including vinyl pyrrolidone and one or more (e.g., two, three,four, five, etc.) other monomeric units that are different than vinylpyrrolidone. In embodiments, in a poly(vinyl pyrrolidone) copolymer, thevinyl pyrrolidone can be the primary monomer (molar quantity), such aspresent in an amount of greater than 50% (mol), 55% (mol) or greater,60% (mol) or greater, 65% (mol) or greater, 70% (mol) or greater, 75%(mol) or greater, 80% (mol) or greater 85% (mol) or greater, 90% (mol)or greater, 92.5% (mol) or greater, 95% (mol) or greater, 97.5% (mol) or99% (mol) or greater. In exemplary embodiments, vinyl pyrrolidone ispresent in the copolymer in the range of about 75% (mol) to about 97.5%(mol), about 85% (mol) to about 97.5% (mol), or about 90% (mol) to about97.5% (mol).

Other monomers that can be copolymerized with vinyl pyrrolidone toprovide the vinyl pyrrolidone polymer include, but are not limited toacrylamide, methacrylamide, acrylic acid,acrylamido-2-methylpropanesulfonate (AMPS), methacrylic acid, methylacrylate, methyl methacrylate, hydroxyethyl methacrylate, hydroxyethylacrylate, glyceryl acrylate, glyceryl methacrylate, ethylene glycol, andderivatives of these monomers.

For example, in some embodiments, the second coated layer includes avinyl pyrrolidone polymer comprising a photoreactive group (e.g.,photo-PVP). Reagents and methods for the preparation of photo-PVP can befound in references such as U.S. Pat. Nos. 4,979,959; 5,002,582;5,263,992; 5,414,075; 5,512,329; and 5,637,460, the teaching of whichare incorporated herein by reference. In some modes of practice,photo-PVP can be formed by the copolymerization of 1-vinyl-2-pyrrolidoneand N-(3-aminopropyl (meth)acrylamide), which then can be derivatizedwith an acyl chloride (such as, for example, 4-benzoylbenzoyl chloride)under Schotten-Baumann conditions. That is, the acyl chloride reactswith the amino group of the N-(3-aminopropyl) moiety of the copolymer.An amide is formed resulting in the attachment of the aryl ketone to thepolymer.

A vinyl pyrrolidone polymer comprising a photoreactive group can also beprepared by copolymerizing vinyl pyrrolidone with a monomer derivatizedwith a photoreactive group. Exemplary monomer derivatives include arylketone derivatives of hydrophilic free radically polymerizable monomerssuch as acrylamide, methacrylamide and AMPS. One exemplarymethacrylamido-based monomer with a pendent photoreactive groups isN-[3-(4-benzoylbenzamido) propyl]methacrylamide (BBA-APMA), thesynthesis which is described in Examples 1-3 of U.S. Pat. No. 5,858,653(Duran et ad.) Another exemplary methacrylamide-based monomer with apendent photoreactive group isN-[3-(7-methyl-9-oxothioxanthene-3-carboxamido)propyl] methacrylamide(MTA-APMA), the synthesis which is described in Examples 1-2 of U.S.Pat. No. 6,156,345 (Chudzik et al.)

In some embodiments, a third coated layer that includes an acidgroup-containing polymer is formed in contact with the second coatedlayer. An “acid group-containing polymer” refers to polymer that hasacid groups presented on the polymer chain. Acidic groups include, forexample, sulfonio acids, carboxylic acids, phosphonic acids, and thelike. Exemplary salts of such groups include, for example, sulfonate,carboxylate, and phosphate salts. Exemplary counter ions include alkali,alkaline earths metals, ammonium, protonated amines, and the like. Ifone or more counter ions are used, the acid groups of the acidgroup-containing polymer are partially neutralized. For example a molarpercentage of the acid groups can be neutralized with counter ions, suchas in the range of x to y, wherein x toy are selected from about 1%, 5%,10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, wherein x isless than y.

Exemplary carboxylic acid-group containing monomers that can be used toprepare the acid group-containing polymer, include, but are not limitedto acrylic acid, methacrylic acid, itaconic acid, monomethyl itaconicacid, maleic anhydride, fumaric acid, and crotonic acid, and saltsthereof. Exemplary sulfonic acid-group containing monomers that can beused to prepare the acid group-containing polymer, include, but are notlimited to acrylamido-2-methylpropanesulfonic acid (AMPS),2-(meth)acylamido-2-methylpropane sulfonic acid, vinyl sulfonic acid,2-sulfoethyl methacrylate, and salts thereof copolymers made from acombination of two or more different acid-group containing monomers canbe used, or copolymers made from one or more acid-group containingmonomers and one or more non-acid group containing monomers can be used.These copolymers can be random copolymers, block copolymers, graftcopolymers or blends thereof.

Other exemplary carboxylic acid-containing monomers that can be used toprepare the acid group-containing copolymers include styrene and maleicanhydride copolymerized to produce styrene-maleic anhydride copolymer(PSMA). Yet other exemplary carboxylic acid-containing monomers aredescribed in “Hydrogen-Bonded Interpolymer Complexes; Formation,Structure and Applications” Chapters 1 and 7, Eds. Vitally V.Khutoryanskiy and Georgios Stalkos (2009).

The acid group-containing polymer may optionally be described withreference to its pH. For example, the acid group-containing polymer mayhave a pH in the range of about 1 to about 5, about 1.2 to about 5,about 1.5 to about 5, about 2.5 to about 5, about 2.75 to about 4.5, orabout 3 to about 4.25.

The third coated layer that is a top coating can comprise an acrylicacid polymer. As used herein an “acrylic acid polymer” refers topolymers including acrylic acid monomeric units. The acrylic acidpolymer can be an acrylic acid homopolymer or a acrylic acid copolymerincluding acrylic acid and one or more (e.g., two, three, four, five,etc.) other monomeric units that are different than acrylic acid. Inembodiments, in a poly(acrylic acid) copolymer, the acrylic acid can bethe primary monomer (molar quantity), such as present in an amount ofgreater than 50% (mol), 55% (mol) or greater, 60% (mol) or greater, 65%(mol) or greater, 70% (mol) or greater, 75% (mol) or greater, 80% (mol)or greater, 85% (mol) or greater, 90% (mol) or greater, 92.5% (mol) orgreater, 95% (mol) or greater, 97.5% (mol) or 99% (mol) or greater. Inexemplary embodiments, acrylic acid is present in the copolymer in therange of about 75% (mol) to about 100% (mol), about 85% (mol) to about100% (mol), about 95% (mol) to about 100% (mol), or about 98% (mol) toabout 100% (mol).

In some embodiments, the acrylic acid polymer in the top coating mayhave an average molecular weight of 150 kDa or greater. In yet otherembodiments the acrylic acid polymer in the top coating may have anaverage molecular weight of 250 kDa or greater, 350 kDa, 450 kDa, 550kDa, 650 kDa or greater or even in some cases an average molecularweight of 750 kDa or greater.

The acrylic acid polymer of the third coated layer can undergo hydrogenbonding with the natural or synthetic polymer, such as a vinylpyrrolidone polymer, of the second coated layer. More specifically,hydrogen bonding between the polymers can involve the carbonyl oxygensof both the pyrrolidone ring and the carboxylic acid.

In other embodiments, the third coated layer that is a top costing alsoincludes a cross-linking agent comprising at least two photoreactivegroups, or an acrylamide polymer comprising at least one photoreactivegroup. In some embodiments, the acrylamide polymer can compriseacrylamide, acrylamido-2-methylpropanesulfonate groups (AMPS), andpoly(ethyleneglycol) groups. For example, in a specific embodiment, theacrylamide polymer can be N-acetylatedpoly[acrylamide-co-sodium-2-acrylamido-2-methylpropanesulfonate-coN-(3-(4-benzoylbenzamido)propyl) methacrylamide]-co-methoxypoly(ethylene glycol) monoethacrylate. Reagents and method for thepreparation of polymers comprising polyacrylamide in accordance withembodiments herein can be found in can be found in references such asU.S. Pat. Nos. 4,979,959; 5,002,582; 5,263,992; 5,414,075; 5,512,329;and 5,637,460, the teaching of which are incorporated herein byreference.

In embodiments, the second or third coated layer, or both, can include acrosslinking reagent comprising photoreactive groups. The photoreactivegroup can be an aryl ketone, such as acetophenone, benzophenone,anthrone, and anthrone-like heterocycles (i.e., heterocyclic analogs ofanthrone such as those having N, O, or S in the 10-position), or theirsubstituted (e.g., ring substituted) derivatives.

Exemplary cross-linking agents are described in U.S. Publ. Pat. App. No.2011/0245367, the content of which is herein incorporated by referencein its entirety. In some embodiments, at least one of the first and/orsecond cross-linking agents may comprise a linking agent having formulaPhoto¹-LG-Photo², wherein Photo¹ and Photo², independently represent atleast one photoreactive group and LG represents a linking groupcomprising at least one silicon or at least one phosphorus atom, thereis a covalent linkage between at least one photoreactive group and thelinking group, wherein the covalent linkage between at least onephotoreactive group and the linking group is interrupted by at least oneheteroatom.

In other embodiments, an ionic photoactivatable cross-linking agent canbe used. The ionic photoactivatable cross-linking agent can be acompound of formula 1: X¹-Y-X² where Y is a radical containing at leastone acidic group, basic group, or a salt of an acidic group or basicgroup. X¹ and X² are each independently a radical containing a latentphotoreactive group.

For example, a compound of formula 1 can have a radical Y that containsa sulfonic acid or sulfonate group; X¹ and X² can contain photoreactivegroups such as aryl ketones. Such compounds include4,5-bis(4-benzoylphenylmethyleneoxy) benzene-1,3-disulfonic acid orsalt; 2,5-bis(4-benzoylphenylmethyleneoxy) benzene-1,4-disulfonic acidor salt; 2,5-bis(4-benzoylphenylmethyleneoxy)benzene-1-sulfonic acid orsalt; N,N-bis[2-(4-benzoylbenzyloxy)ethyl]-2-aminoethane-sulfonic acidor salt, and the like. See U.S. Pat. No. 6,278,018

In other embodiments of formula 1, Y can be a radical that contains abasic group or a salt thereof. Such Y radicals can include, for example,an ammonium, a phosphonium, or a sulfonium group; suitable counter ionsinclude, for example, carboxylates, halides, sulfate, and phosphate.Exemplary photoactivatable cross-linking agents includeethylenebis(4-benzoylbenzyl-dimethylammonium) salt; hexamethylenebis(4-benzoylbenzyl-dimethylammonium) salt;1,4-bis(4-benzoylbenzyl)-1,4-dimethylpiperazinediium) salt,bis(4-benzoylbenzyl)hexamethylenetetraminediium salt,bis[2-(4-benzoylbenzyl-dimethylammonio)ethyl]-4-benzoylbenzylmethylammoniumsat; 4,4-bis(4-benzoylbenzyl)morpholinium salt;ethylenebis[(2-(4-benzoylbenzyldimethyl-ammonio)ethyl)-4-benzoylbenzylmethylammonium] salt; and1,1,4,4-tetrakis(4-benzoylbenzyl)piperzinediium salt. See U.S. Pat. No.5,714,360.

Substrates on which the coating can be formed can be partially orentirely fabricated from a metal, ceramic, glass, or the like, or acombination thereof. Substrates can include polymers such aspolyurethanes and polyurethane copolymers, polyethylene, polyolefins,styrene-butadiene copolymers, polyisoprene, isobutylene-isoprenecopolymers (butyl rubber), including halogenated butyl rubber,butadiene-styrene-acrylonitrile copolymers, silicone polymers,fluorosilicone polymers, polycarbonates, polyamides, polyesters,polyvinyl chloride, polyether-polyester copolymers, polyether-polyamidecopolymers, and the like. The substrate can be made of a singlematerial, or a combination of materials.

Substrate polymers can also include those formed of synthetic polymers,including oligomers, homopolymers, and copolymers resulting from eitheraddition or condensation polymerizations. Examples of suitable additionpolymers include, but are not limited to, acrylics such as thosepolymerized from methyl acrylate, methyl methacrylate, hydroxyethylmethacylate, hydroxyethyl acrylate, acrylic acid, methacylic acid,glyceryl acrylate, glyceryl methacrylate, methacrylamide, andacrylamide; vinyls such as ethylene, propylene, vinyl chloride, vinylacetate, vinyl pyrrolidone, vinylidene difluoride, and styrene. Examplesof condensation polymers include, but are not limited to, nylons such aspolycaprolactam, polylauryl lactam, polyhexamethylene adipamide, andpolyhexamethylene dodecanediamide, and also polyurethanes,polycarbonates, polyamides, polysulfones, poly(ethylene terephthalate),polydimethylsiloxanes, and polyetherketone.

In some embodiments, the substrate includes a polymer selected from thegroup consisting of polyamide, polyimide, polyether block amide (PEBAX),polyether ether ketone (PEEK), high density polyethylene (HDPE),polyethylene, polyurethane, and polyethylene vinyl acetate.

Metals that can be used as substrates in medical articles includeplatinum, gold, or tungsten, as well as other metals such as rhenium,palladium, rhodium, ruthenium, titanium, nickel, and alloys of thesemetals, such as stainless steel, titanium/nickel, nitinol alloys, cobaltchrome alloys, non-ferrous alloys, and platinum/iridium alloys. Oneexemplary alloy is MP35.

Exemplary medical articles include vascular implants and grafts, grafts,surgical devices; synthetic prostheses; vascular prosthesis includingendoprosthesis, stent-graft, and endovascular-stent combinations; smalldiameter grafts, abdominal aortic aneurysm grafts; wound dressings andwound management device; hemostatic barriers; mesh and hernia plugs;patches, including uterine bleeding patches, atrial septic defect (ASD)patches, patent foramen ovale (PFO) patches, ventricular septal defect(VSD) patches, and other generic cardiac patches; ASD, PFO, and VSDclosures; percutaneous closure devices, mitral valve repair devices;left atrial appendage filters; valve annuloplasty devices, catheters;central venous access catheters, vascular access catheters, abscessdrainage catheters, drug infusion catheters, parenteral feedingcatheters, intravenous catheters (e.g., treated with antithromboticagents), stroke therapy catheters, blood pressure and stem graftcatheters; anastomosis devices and anastomotic closures; aneurysmexclusion devices; biosensors including glucose sensors; cardiacsensors; birth control devices; breast implants; infection controldevices; membranes; tissue scaffolds; tissue-related materials; shuntsincluding cerebral spinal fluid (CSF) shunts, glaucoma drain shunts;dental devices and dental implants; ear devices such as ear drainagetubes, tympanostomy vent tubes; ophthalmic devices; cuffs and cuffportions of devices including drainage tube cuffs, implanted druginfusion tube cuffs, catheter cuff, sewing cuff spinal and neurologicaldevices; nerve regeneration conduits; neurological catheters;neuropatches; orthopedic devices such as orthopedic joint implants, bonerepair/augmentation devices, cartilage repair devices; urologicaldevices and urethral devices such as urological implants, bladderdevices, renal devices and hemodialysis devices, colostomy bagattachment devices; biliary drainage products, vena cave filters, andembolic protection filters and devices and electrophysiology mapping andablation catheters.

The coating having the first oligomerized polyphenol, the second layerincluding the synthetic or natural polymer hydrogen bonded to theoligomerized polyphenol, and optionally the third layer acid polymer canhave a hemocompatible (blood compatible) property. For example, amedical article with a hemocompatible costing can reduce effects thatmay associated with placing a foreign object in contact with bloodcomponents, such as the formation of thrombus or emboli (blood clotsthat release and travel downstream). The hemocompatible property of thecoating can be observed as compared to a medical device that does nothave the coating. Optionally, the coating can be further modified withhemocompatible proteins or peptides to enhance the hemocompatible (bloodcompatible) property.

An assay for measuring hemocompatibility of a coated surface can beperformed using any one of a variety of tests. Techniques, such asincluding clot-based tests, such an artificial circulation (Chandlerloop) using whole blood augmented with platelets (e.g., see Robbie, L.A., et al. (1997) Thromb Hemost. 77:510-5), or the in vitro bovine bloodloop, chromogenic or color assays, direct chemical measurements, andELISAS, are used for coagulation testing (e.g., see. Bates, S. M., andWeitz, J J. (2005) Circulation, 112:53-60; and Walenga, J. M., et al.(2004) Semin Thromb Hemost. 30:683-695). Whereas clotting assays providea global assessment of coagulation function, chromogenic tests aredesigned to measure the level or function of specific factors.

In some embodiments, the coating includes with first (polyphenol) andsecond layers, with the second layer comprising a polymer that ishydrogen bonded to the first layer, and that also provides a lubriciousor low friction surface. The lubricious or low friction surface canfacilitate movement of the coated device in relation to a tissue, or canfacilitate movement of the coated device in contact with anothercomponent of the medical device, or movement of two medical devices incontact with each other. For example, one approach to reducing thefriction between a medical device and the environment surrounding themedical device is to apply a lubricious or low friction coating onto themedical device.

The present disclosure may be better understood with reference to thefollowing examples. These examples are intended to be representative ofspecific embodiments of the disclosure, and are not intended as limitingthe scope of the disclosure.

It should be noted that, as used in this specification and the appendedclaims, the singular forms “a,” “an,” and “the” include plural referentsunless the content clearly dictates otherwise. Thus, for example,reference to a composition containing “a compound” includes a mixture oftwo or more compounds. It should also be noted that the term “or” Isgenerally employed in its sense including “and/or” unless the contentclearly dictates otherwise.

It should also be noted that, as used in this specification and theappended claims, the phrase “configured” describes a system, apparatus,or other structure that is constructed or configured to perform aparticular task or adopt a particular configuration to. The phrase“configured” can be used interchangeably with other similar phrases suchas arranged and configured, constructed and arranged, constructed,manufactured and arranged, and the like.

All publications and patent applications in this specification areindicative of the level of ordinary skill in the art to which thedisclosure pertains. All publications and patent applications are hereinincorporated by reference to the same extent as if each individualpublication or patent application was specifically and individuallyindicated by reference. Nothing herein is to be construed as anadmission that the inventors are not entitled to antedate anypublication and/or patent, including any publication and/or patent citedherein.

The disclosure has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variation and modifications may be made while remaining withinthe spirit and scope of the disclosure.

Example 1: Preparing a Low-Protein Binding Polyphenol Coating

First, a tannic acid tie layer was applied to 7 cm segments ofpolyurethane (PU) 7F catheters (Solomon Scientific). To prepare a 2mg/ml tannic acid (TA) solution, 80 mg of TA was dissolved in 40 ml ofan aqueous buffer solution containing 0.5 M NaHCO3 and 0.5 M NaCl (finalpH of 8.3). Catheter segments were added to the tannic acid solution andgently inverted to remove any trapped air bubbles from the catheterlumens. The catheters were then incubated at 50° C. for one hour withoutagitation. After the incubation, catheter segments were removed fromtannic acid, rinsed thoroughly with water, both internal and outerdiameters, and air dried.

Next, for the second layer of the coating, polyvinylpyrrolidone (PVP)was hydrogen bonded to the TA tic layer. TA modified catheters wereplaced into a PVP solution (K30, BASF, 10 mg/ml in 10 mM phosphoricacid, pH 2.0) for five minutes at room temperature, rinsed with water,and air dried.

Lastly, for the third layer, poly(acrylic acid) (PAA) was hydrogenbonded to the PVP layer. Catheter segments were incubated in a PAAsolution (in-house synthesized PAA, 20 mg/ml in water) for five minutesat room temperature. Catheters were then rinsed with water and allowedto air dry at room temperature.

To confirm the presence of the coating, samples of catheter were stainedwith a positively charged dye, toluidine blue, by submerging the samplein 0.1% w/v toluidine blue water solution for five minutes and thenthoroughly rinsing the sample with water to remove excess stain. Thesample stained a dark purple indicating the presence of the negativelycharged PAA top coat. An uncoated control stained a very faint bluewhereas a TA-only control stained a darker blue. A coating without thePAA top coat stained similar to the TA-only control.

Example 2: Fibrinogen Adsorption to Polyphenol Coatings from HumanPlasma

To characterize the protein adsorption properties of the coatings,fibrinogen adsorption to coated and uncoated catheters was quantifiedusing an ELISA technique. Polyurethane catheters were cut into 1 cm longsamples and placed in 12×75 mm glass test tubes (4 samples/test tube).Human platelet-poor plasma (PPP from George King Bio-Medical) wasdiluted 1:4 with phosphate-buffered saline (PBS). Two milliliters ofdiluted PPP was added to each test tube. Samples were incubated for twohours with agitation on an orbital shaker at room temperature. Theplasma was aspirated off of the samples and the samples were washedthree times with a PBS wash solution containing 0.05% (v/v) Tween 20, pH7.4. Next, two milliliters of polyclonal anti-human-fibrinogn-HRP(Rockland, Inc., product #200-103-240) was added to each test tube at adilution of 1:10,000 in PBS. Samples were incubated for 30 minutes withagitation on an orbital shaker at room temperature. The antibodysolution was aspirated off and the samples were washed three times withPBS plus Tween-20 wash solution.

Samples were transferred to clean 12×75 mm glass test tubes (1sample/test tube) and 1 ml of tetramethylbenzidine (TMB) substratesolution was added to each test tube. The samples were incubated for 15minutes with agitation on an orbital shaker at room temperature. Thesupernatant was then transferred to a 96-well microtiter plate and theabsorbances at 650 nm were read on a spectrophotometer (MolecularDevices, Thermomax microplate reader) with a negative control solution,containing only the chromogen, used as the blank. The absorbances aredirectly proportional to the surface concentration of HRP and,therefore, also proportional to the concentration of fibrinogen bound tothe surface of the materials.

To measure the durability of the coatings, a few coated catheters wereincluded that were subjected to a nitrile gloved finger test. The testconsisted of rubbing the sample five times in one direction using lightto moderate pressure while the samples were under a stream of water. Thesample was rotated about a quarter turn after each rub so that theentire circumference was rubbed at least once.

As shown in the graph of FIG. 4 the PAA coating reduced fibrinogenadsorption compared to uncoated PU catheter, whereas the TA coatingsubstantially increased fibrinogen adsorption. In both cases, rubbingthe coating did not have any significant effect.

Example 3: Human Plasma Clotting Times of Polyphenol Coatings

A useful test in determining the hemocompatibility of a surfacemodification is the partial thromboplastin time (PTT) test. The PTT is atest of the intrinsic (factors VIII, IX, XI, and XII) and common(fibrinogen, prothrombin, factors V and X) pathways of coagulation.

Polyurethane catheters were cut into 0.7 cm long samples and each samplewas placed into a 12×75 mm polystyrene test tube. Next, a mixture ofplasma and cephalin (a phospholipid platelet substitute) was dispensedto each test tube. Samples were then incubated at 37° C. for 20 minutes.Transferred 200 μl of plasma from each test tube to a 96-well microtiterplate and added 100 μl of warm CaCl2 to each well. Immediately beganreading OD at 340 nm every 20 seconds. The time at half maximumabsorbance was reported as the clotting time.

As shown in the graph of FIG. 5, a glass control was used as aprocoagulant surface and it clotted in less than five minutes. The TAcoating clotted twice as fast as the uncoated PU control. Adding thehydrogen bonded PVP K30 and PAA layers significantly slowed the clottingtimes.

Example 4: Coatings for Immunoassay on 96-Well Microtiter Plates

Nunc maxisorb (polystyrene treated for optimum protein adsorption) andGreiner UV-Star (cyclic polyolefin) 96-well microtiter plates werecoated with tannic acid and then evaluated in a model immunoassay.

Tannic acid was added to pro-warmed (55° C.) 0.5 M sodium carbonate (pH8.3) containing 0.5 M NaCl at a tannic acid concentration of 2 g/L. Onehundred microliters of this solution was added to each well of theplate, the plate was incubated at 55 C for 5 minutes. The wells wereemptied and than washed 4 times with DI water. The plate was allowed todry. Plates were coated by putting 100 μl/well of rabbit antihorseradish peroxidase (HRP) antibody (Accurate Chemical and Scientific)at 0.86 μg/ml in either of three buffers. The three buffers were 0.05 Msodium carbonate (pH 9.5), phosphate buffered saline (pH 7.2), and 50 mMsodium acetate (pH 5.4). Plates were incubated overnight at roomtemperature, washed 3× with PBS-Tween20, and 100 μl of StabilCoat(SurModics, Inc.) was added to each well. After a 2 hour incubationplates were aspirated and dried at low humidity. The plates were thenused in a model assay that uses horseradish peroxidase (HRP) as theanalyte. Plates were washed three times with PBS-Tween20. HRP (100 μl)was added at 25, 50, 100, 1000, or 10,000 pg/ml in PBS-Tween20 to wells.The plate was incubated for 2 hours and then washed 6× with PBS-Tween20.TMB microwell substrate (SurModics, Inc.) was added to the wells (100μl) and the plate incubated for 20 minutes. Nova-Stop reagent(SurModics, Inc.) (100 μl) was added to the wells and the plate was readat 450 nm. FIGS. 6B and D show that the tannic acid coating vastlyimproved the assay results on the UV-Star plate and slightly improvedthe assay results on a plate (MaxiSorb) already optimized for ELISAassays.

1-20. (canceled)
 21. A medical device comprising a hemostatic coatingcomprising oligomerized polyphenol, the device configured so theoligomerized polyphenol comes in contact with a body fluid.
 22. Themedical device of claim 21 selected from the group consisting ofvascular implants and grafts, wound dressings and wound managementdevice, hemostatic barriers, occlusion articles, mesh and hernia plugs,patches, and uterine bleeding patches.
 23. A method for promotingclotting at a target location in or on the body comprising placing themedical device of claim 21 in or on a target location in the body,wherein the coating contacts body fluid and promotes clotting at thetarget location.
 24. The method of claim 23 wherein the coating promotesfibrinogen absorption.
 25. An article configured for use in an in vitrodiagnostic assay or cell culture, the article comprising a coatingcomprising oligomerized polyphenol.
 26. The article of claim 25 which isan ELISA plate, a microfluidics device, or a diagnostic slide.
 27. Thearticle of claim 25 wherein the coating comprising oligomerizedpolyphenol is passivated with a synthetic or natural polymer, whereinthe synthetic or natural polymer is hydrogen bonded to the oligomerizedpolyphenol.
 28. A diagnostic kit comprising the article for use in an invitro diagnostic assay of claim
 25. 29. A method for promotingadsorption of a biological macromolecule to a surface of an article inan in vitro diagnostic assay or cell culture, comprising steps ofcontacting the article of claim 25 comprising the coating comprisingoligomerized polyphenol with a composition comprising a biologicalmacromolecule, wherein the coating promotes adsorption of the biologicalmacromolecule to the oligomerized polyphenol via hydrogen bonding. 30.The method of claim 29, wherein the biological macromolecule is apeptide, protein, nucleic acid, or polysaccharide.
 31. The method ofclaim 30, wherein the protein is an antibody or antibody fragment, or ananalyte that is a peptide or protein.
 32. The method of claim 31 whereinthe method is an ELISA.
 33. A medical device comprising an inner surfacecomprising a coating, the coating comprising oligomerized polyphenol.34. The medical device of claim 33 wherein the coating is formed on theinner diameter of a catheter.
 35. A method for reducing or preventingthe adherence of bacteria on a medical device surface, comprisingimplanting the device of claim 33 in a patient.
 36. The medical deviceof claim 21 wherein the oligomerized polyphenol comprises (a) apolyphenol having a molecular weight in the range of 500-4000 Da, (b) apolyphenol having 12 or more phenolic hydroxyl groups, or both (a) and(b).
 37. The medical device of claim 21 wherein (a) the oligomerizedpolyphenol comprises a polyphenol derived from esterification of acomposition comprising gallic acid, (b) oligomerized polyphenolcomprises tannic acid, or both (a) and (b).
 38. The medical device ofclaim 21 wherein the oligomerized polyphenol comprises an inorganicmetal ion that crosslinks polyphenols.